WO2003082815A1

WO2003082815A1 - Method of heightening optical purity of 1-benzyl-3-aminopyrrolidine and salt for use therein

Info

Publication number: WO2003082815A1
Application number: PCT/JP2003/003933
Authority: WO
Inventors: Fumihiko Kano; Natsuki Mori
Original assignee: Kaneka Corporation
Priority date: 2002-03-29
Filing date: 2003-03-28
Publication date: 2003-10-09
Also published as: JP4481659B2; EP1491530A4; US20040249169A1; US20080255371A1; EP1491530A1; US7268236B2; JPWO2003082815A1; EP1491530B1; DE60333741D1

Abstract

A method for heightening the optical purity of 1-benzyl-3-aminopyrrolidine having a low optical purity using an inexpensive reagent through a simple procedure. The method, which is for heightening the optical purity of 1-benzyl-3-aminopyrrolidine, comprises converting 1-benzyl-3-aminopyrrolidine into a 1:1 by mole salt thereof with an optically inactive acid and separating out the salt as crystals. Also provided is a salt of 1-benzyl-3-aminopyrrolidine which is for use in the method.

Description

Specification

(1) Method for improving optical purity of 3-aminopyrrolidine and salts used therein

The present invention relates to a method for improving the optical purity of 1-benzyl-13-aminovirolidine, which is useful as an intermediate for synthesizing fine chemicals such as pharmaceuticals and agricultural chemicals. The present invention also relates to a novel salt of 1-benzyl-13-aminopyrrolidine used for improving optical purity. Background art

As a method for improving the optical purity of 1-benzyl-3-aminopyrrolidine, a method of optically resolving racemic 1-benzyl-3-aminopyrrolidine using an optically active carboxylic acid derivative (Japanese Patent Laid-Open No. — Japanese Patent Application Laid-Open No. H09-124595, Japanese Patent Laid-Open No. 09-1766), a method for optical resolution with an optically active amino acid derivative or an optically active tartaric acid derivative. There is known a method of optical resolution with an optically active camphorsulfonate (Japanese Patent Application Laid-Open No. H09-216686), all of which are difficult to obtain. Since an expensive optically active optical resolving agent is used, there is a problem as an industrial method.

On the other hand, attempts have been made to obtain optically active 1-benzyl-13-aminopyrrolidine by using optically active raw materials and derivatizing them. Racemization is often unavoidable, and it is difficult to obtain 1-benzyl-13-aminopyrrolidine having high optical purity (Japanese Patent Application Laid-Open No. 2000-53642, Japanese Patent Application Laid-Open No. 0 7—5 0 6 11 10 Publication). It has been desired to develop a method for improving the optical purity of 1-benzyl-3-aminopyrrolidine of low optical purity obtained by these methods.

As the salts of 1-benzyl-13-aminobirolidine, in addition to the salts with the above-mentioned optically active acids, racemic 1-benzyl-1-monoaminopyrrolidine monohydrochloride (tetrahedron letters 4 2 (2001) 56445), an optically active 1-benzyl-3-aminopyrrolidine dihydrochloride (Japanese Patent Application Laid-Open No. H02-2186864), In addition, racemic 1-benzyl-3-aminopyrrolidine monofumarate is known, but there is no report that the optical purity was improved by forming these salts.

As described above, there has been no known method for improving the optical purity of low-optical-purity 1-benzyl-13-aminopyrrolidine by using an inexpensive reagent and performing a simple operation. Summary of the Invention

In view of the above, an object of the present invention is to provide a method for improving the optical purity of low-purity 1-benzyl-3-aminopyrrolidine by a simple operation using an inexpensive reagent. is there.

As a result of intensive studies to solve the above-mentioned problems, 1-benzyl-3-aminopyrrolidine was converted to a 1 mol to 1 mol salt with a non-optically active acid, and the salt was obtained as a crystal, which was inexpensive and simple. It was further discovered that 1-benzyl-3-aminopyrrolidine with improved optical purity could be obtained, and the present invention was completed.

That is, the present invention is characterized in that 1-benzyl-3-aminopyrrolidine is converted to a salt of 1 mol to 1 mol with a non-optically active acid, and the salt is obtained as crystals. —A method for improving the optical purity of aminopyrrolidine.

Further, the present invention provides the following general formula (1)

(Wherein, HX represents hydrobromic acid, methanesulfonic acid, or acetic acid). Detailed Disclosure of the Invention

Hereinafter, the present invention will be described in detail.

The method for improving the optical purity of 1-benzyl-3-aminopyrrolidine according to the present invention comprises the steps of: 1-benzyl-3-aminopyrrolidine, in particular, its optically active compound is prepared by converting 1 mol to 1 mol of a salt with a non-optically active acid. And the salt is obtained as crystals.

The low optical purity 1-benzyl-13-aminopyrrolidine that can be used in the present invention is, for example, as described in JP-A-2000-53642, as disclosed in A method in which a substituted butane derivative is converted into a pyrrolidine derivative in the presence of a primary amamine and then further reacted under pressure in the presence of an amine, and a method described in Japanese Patent Application Laid-Open No. 07-5061010. As described above, L-aspartic acid having a protected amino group can be reduced, reacted with thionyl halide or the like, further reacted with amine to form a pyrrolidine derivative, and then deprotected. .

Examples of the non-optically active acid used in the present invention include mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid; organic sulfonic acids such as methanesulfonic acid; and carboxylic acids such as acetic acid. . These acids can be used alone or in combination of two or more. Of these acids, monovalent acids such as hydrochloric acid, hydrobromic acid, methanesulfonic acid, and acetic acid are easily formed because they easily form 1 mol to 1 mol salt with 1 benzyl 3-aminopyrrolidine. In addition, hydrobromic acid and methanesulfonic acid are more preferable from the viewpoints of crystal physical properties such as low hygroscopicity of crystals and good filterability. The amount of the non-optically active acid used is not particularly limited as long as it can be used to form a salt with 1 mol of 1-benzylpyrrolidine and 1 mol of 1 mol and precipitate as a crystal. However, it is possible to obtain an excellent effect of improving optical purity without forming 1 mol to 2 mol of salt with 1-benzyl-3-aminopyrrolidine. It is preferably 0.1 to 1 molar equivalent, more preferably 0.5 to 0.9 molar equivalent. In addition, by using an amount of 1 molar equivalent or less with respect to the optical isomer having a larger amount of 1-benzyl-3-aminopyrrolidine, the effect of improving the optical purity can be maximized.

The method for improving optical purity of the present invention is preferably carried out in a solvent. Solvents that can be used in the present invention include, for example, isopropanol, ethanol, methanol Alcohols such as alcohols; polyhydric alcohols such as ethylene glycol / propylene glycol and propylene dalicol; esters such as ethyl acetate and methyl acetate; hydrocarbons such as toluene and hexane; getyl ether and tetrahydrofuran. And ethers such as methyl t-butyl ether; polyethers such as glyme; halogenated hydrocarbons such as methylene chloride; amides such as dimethylformamide; sulfoxides such as dimethyl sulfoxide; be able to. Preferred examples include esters such as ethyl acetate, hydrocarbons such as toluene and hexane, alcohols such as isopropanol and ethanol, and water. These solvents may be used alone or in combination of two or more.

The type, amount and mixing ratio of these solvents may be selected according to the solubility of the salt to be obtained.

Next, examples of a method for crystallizing a salt of 1 mol of 1-benzyl-3-aminopyrrolidine with a non-optically active acid in a molar ratio of 1 mol include the following methods.

1) 1 Benzyl 3-Aminopyrrolidine is mixed with an aqueous solution of a non-optically active acid, followed by concentration and crystallization by removing water. In this case, a solvent capable of azeotropic distillation with water (eg, ethyl acetate, toluene, etc.) can be used, and water can be distilled off by an azeotropic effect.

2) A method of crystallizing by mixing 1-benzyl-3-aminopyrrolidine with a non-optically active acid in a solvent.

3) After mixing 1-benzyl-3-aminopyrrolidine and a non-optically active acid in a solvent, or dissolving a salt of 1-benzyl-3-aminopyrrolidine and a non-optically active acid in the solvent, Cooling and crystallizing.

4) 1-Penzinolate 3-aminopyrrolidine and a non-optically active acid are mixed in a solvent, or after dissolving a salt of 1-benzoyl 3-amino-pyrrolidine and a non-optically active acid in a solvent. A method of crystallizing by adding or replacing a poor solvent with a poor solvent.

The above method may be appropriately selected depending on the combination of the type of salt and the solvent. For example, when using an acid which can be easily used as an aqueous solution such as hydrochloric acid, hydrobromic acid, etc., the method of 1) can be easily used as an ordinary non-water-containing substance such as methanesulfonic acid and acetic acid. When an acid is used, it is preferable to select the method 2). Further, the slurry solution of the salt obtained by the method of 1) or 2) is redissolved by the method of 3), then cooled and crystallized, etc., 1), 2), 3), 4) Crystallization can also be carried out by appropriately combining the above methods.

Examples of the solvent used in the above 2) to 4) include the same solvents as those described above. Examples of the poor solvent used in 4) include toluene and hexane.

Examples of the salt of 1-benzyl-3-aminopyrrolidine and the non-optically active acid in the above 3) to 4) include, for example, the method described in the present invention (the above 1) and 2), the above 3), Of 4), a method of mixing 1-benzyl-13-aminopyrrolidine and a non-optically active acid in a solvent) to obtain a salt of 1-benzyl-3-aminopyrrolidine and the non-optically active acid again. It may be used, or when 1-benzyl-3-aminopyrrolidine is synthesized, a salt of 1-benzyl-3_aminopyrrolidine and a non-optically active acid is produced by coexisting a non-optically active acid. You may use the one that was made.

When dissolving a salt of 1-benzyl-13-aminopyrrolidine and a non-optically active acid in a solvent, for example, heating or the like can also be performed. The heating temperature in this case is not particularly limited, but may be appropriately set to a temperature at which 1-benzyl-3-aminopyrrolidine and the non-optically active acid are dissolved in the type of solvent or mixed solvent used. The crystallization temperature in the crystallization method of the above 1) to 4) may be appropriately selected depending on the type of salt and the type of solvent used, and is not particularly limited.Preferably, the type of solvent or mixed solvent used is (1) The temperature may be lower than the temperature at which 3-aminopyrrolidine and the non-optically active acid dissolve, and may be set appropriately according to the target amount of precipitation. The crystals of the salt of 1 mol to 1 mol of 1-benzyl-13-aminopyrrolidine and the non-optically active acid precipitated by the above-mentioned crystallization method can be separated and obtained by a filtration operation or the like.

The 1-to-1 mole salt of 1-benzyl-3-aminopyrrolidine and non-optically active acid, which has been crystallized by the above method and has improved optical purity, has improved chemical purity as well as optical purity. Used as a raw material for fine chemicals such as pharmaceuticals and agricultural chemicals However, by treating with a base such as an alkali metal hydroxide to release 1-benzyl-3-aminopyrrolidine, the optical purity can be increased by performing operations such as extraction, concentration, and distillation. It can also be obtained as 1-benzyl-3-aminopyrrolidine oil.

Among the 1 mol to 1 mol salt of 1-benzyl-3-aminopyrrolidine and a non-optically active acid, the following formula (1)

(Wherein, HX represents hydrobromic acid, acid, or acetic acid), a salt with hydrobromic acid, acid, or acetic acid, particularly an optically active form thereof, is prepared by the present inventors. It is a novel compound that has been found to be useful in a method for improving the optical purity of 1-benzyl-3-aminopyrrolidine. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to only these Examples.

The optical purity in the following examples was determined by the following method. 0.18% 1 Benzyl 3-aminopyrrolidine in acetonitrile solution 0.1 ml (When analyzing the salt of 1-benzyl-3-aminopyrrolidine with a non-optically active acid, dissolve the salt in water. Dissolved in water, made sodium hydroxide by adding sodium hydroxide, extracted with toluene, and concentrated to obtain an oil of 1-benzyl 3-aminovirolidine), and 0.4% GI TC (GI TC: Add 0.2 mL of 2,3,4,6-tetra-O-acetinol β-D-glucopyranosyl thiocyanate) in acetonitrile, react at room temperature for 10 minutes, and then add 0.2% ethanol. Amin's Acetonito 0.1 mL of the rill solution was added and left for 3 minutes, and then diluted with 1.0 mL of a 0.05% phosphoric acid aqueous solution to obtain a sample solution. Was injected into HPLC, and the optical purity was measured based on the area ratio. The column used for the analysis was CAPCELL PAK C 18 SG 120 (SI SE IDO) 4.6 mm φ X 250 mm, and the mobile phase was ρ H 4 aqueous solution (0.03% aqueous ammonia plus 5% acetic acid aqueous solution Aqueous solution adjusted to Η4) Ζmethanol = 62Ζ38 (volume ratio) was used. The flow rate was 1. OmL / min, the column temperature was 30 ° C, and the detection was performed at UV 254 nm. The GITC derivative of (R) _1-benzyl-3-aminopyrrolidine is 25.5 minutes, and the derivative of (S) -l-benzyl-3-aminopyrrolidine GITC is 28.5 minutes. Was detected.

(Example 1)

1.50 g of 1-benzyl-3-aminopyrrolidine having a chemical purity of 89.9 wt% and an optical purity of 88.8% e e (R-isomer excess) was dissolved in 10 g of ethyl acetate. 0.75 g of concentrated hydrochloric acid (1.0 molar equivalent to (R) -11-benzyl-13-aminopyrrolidine) was added. The solution was concentrated under reduced pressure to remove water. 2 OmL of ethyl acetate was added to the concentrate, which was concentrated again. Ethyl acetate (2 OmL) was added to the obtained concentrate to cause crystallization. The crystals were filtered and dried to obtain 1.48 g of 1-benzyl-3-aminopyrrolidine monohydrochloride. The optical purity was improved to 93.6% e e (excess R form).

(Example 2)

In the same manner as in Example 1 except that 1.21 g of 48% hydrobromic acid (1.0 mol equivalent to (R) _1-benzyl-3-aminopyrrolidine) was used instead of concentrated hydrochloric acid, There was obtained 1.68 g of 1-benzyl 3-aminopyrrolidine monohydrobromide. The optical purity was improved to 96.0% e e (R-isomer excess).

1-benzyl-1-3-aminopyrrolidine monohydrobromide

Melting point: 103 ~: L07 ° C

IR (KBr) cm—2149, 1613, 1526, 1467, 1408, (Example 3)

1.51 g of 1-benzyl-3-aminopyrrolidine having a chemical purity of 89.9 wt% and an optical purity of 88.8% e e (R-isomer excess) was dissolved in 10 g of ethyl acetate. 0.41 g of acetic acid (0.94 molar equivalents based on (R) -1-benzyl-3-aminopyrrolidine) was added. Hexane (3 OmL) was added to the solution for crystallization. The crystals were filtered and dried to obtain 1.48 g of 1-benzoyl 3-aminovirolidine monoacetate. The optical purity was improved to 93.4% e e (R-isomer excess).

1-benzyl-1-3-aminopyrrolidine monoacetate

Melting point: 90 ~ 95 ° C

IR (KBr) ^cm_1 : 2224, 1647, 1541, 1474, 1352, 1154

(Example 4)

1.42 g of 1-benzyl-3-aminopyrrolidine having a chemical purity of 89.9 wt% and an optical purity of 88.8% e e (R-form excess) was dissolved in 5 g of ethyl acetate. A solution of 0.49 g of methanesulfonic acid (0.75 molar equivalents based on (R) -11-benzyl-3-aminopyrrolidine) in 5 g of ethyl acetate was added. Crystals precipitated with the addition. The crystals were filtered and dried to obtain 1.40 g of 1-benzoyl 3-aminopyrrolidine 1-methanesulfonate. The optical purity was improved to 95.4% e e (R excess).

1-benzyl-3-aminovirolidine monomethanesulfonate

Melting point: 97 ~: L 02 ° C

I R (KB r) cm—2149, 1615, 1549, 1453, 1240, 1148

(Example 5)

3.38 g of 1-benzinole-3-aminopyrrolidine having a chemical purity of 100 wt% and an optical purity of 90.5% ee (R-isomer excess) was dissolved in 15 g of isopropanol. 48 3.05 g (0.99 molar equivalents based on (R) -11-benzyl-13-aminopyrrolidine) of% hydrobromic acid was added. About 5 g was concentrated and distilled off under reduced pressure to remove water, and crystallized by stirring at room temperature. The crystals were filtered and dried to obtain 0.95 g of 1-benzyl-3-aminopyrrolidine monohydrobromide. The optical purity was improved to 99.6% ee (R-isomer excess).

(Example 6)

One 0.17 g of 1-benzyl-3-aminopyrrolidine having a chemical purity of 90.3 wt% and an optical purity of 89.8% e e (R-isomer excess) was dissolved in 30 g of ethanol. 7.84 g of 48% hydrobromic acid (0.94 molar equivalents based on (R) _1-benzyl-3-aminopyrrolidine) was added. After concentration and dehydration under reduced pressure, 59 g of ethyl acetate was added for crystallization. The obtained slurry was heated to about 70 ° C. to completely dissolve the crystals. The resulting solution was crystallized by slow cooling. The crystals were filtered and dried to give 1-benzyl-3-aminopyrrolidine monohydrobromide, 6.15 g. The optical purity was improved to 100% e e (R excess).

(Example 7)

10.17 g of 1-benzyl 3-aminopyrrolidine having a chemical purity of 90.3 wt% and an optical purity of 89.8% e e (R-isomer excess) was dissolved in 30 g of ethanol. 4.47 g of methane sulfonic acid (0.94 molar equivalents based on (R) -1 benzyl-3-aminopyrrolidine) was added. After distilling off ethanol under reduced pressure, crystallization was performed by adding 54 g of ethyl acetate. The resulting slurry was heated to about 79 ° C to completely dissolve the crystals. The resulting solution was slowly cooled and crystallized. The crystals were filtered and dried to obtain 12.12 g of 1 benzene / 3-aminopyrrolidine, 1 methance / lefonate. The optical purity was improved to 96.1% e e (R-isomer excess).

Dissolve 2 g of the obtained methanesulfonate of 1-benzenepyrrolidine 3-aminopyrrolidine in 5 mL of water, add 30% sodium hydroxide, and add Aminopyrrolidine was released. The solution was extracted with 2 OmL of toluene and concentrated to obtain 1.10 g of 1-benzyl-3-aminopyrrolidine as an oil. Industrial applicability

According to the present invention, as described above, it is possible to improve the optical purity of low-optical-purity 1-benzinole-3-aminopyrrolidine by a simple operation using an inexpensive reagent.

Claims

The scope of the claims

1.1. Benzyl 3-aminopyrrolidine, which is obtained by converting 1-benzyl 3-aminopyrrolidine to a 1 mol to 1 mol salt with a non-optically active acid, and obtaining the salt as a crystal. Method for improving optical purity.

2. The method according to claim 1, wherein 2.1-benzyl-3-aminopyrrolidine is an optically active substance.

3. The method according to claim 2, wherein the amount of the non-optically active acid used is 1 molar equivalent or less with respect to the optical isomer having a larger content of 1-benzyl-3-aminopyrrolidine.

4. The method according to any one of claims 1 to 3, wherein the non-optically active acid is used as an aqueous solution, and concentrated and dehydrated for crystallization.

5.1 The method according to any one of claims 1 to 3, wherein the mixture is crystallized by mixing 1-benzyl-1-^-aminopyrrolidine with a non-optically active acid in a solvent.

6.1 Ability to mix 1-benzyl-3-aminopyrrolidine and non-optically active acid in a solvent or a solvent of 1-benzyl-3-aminopyrrolidine and a non-optically active acid salt The method according to any one of claims 1 to 3, wherein the crystallization is carried out after dissolving in water.

7.1 Ability to mix 1-benzyl-3-aminopyrrolidine and a non-optically active acid in a solvent or a salt of 1-benzyl-3-aminopyrrolidine and a non-optically active acid in a solvent The method according to any one of claims 1 to 3, wherein after dissolution, crystallization is performed by adding or replacing the poor solvent.

8. Non-optically active acids include hydrochloric acid, hydrobromic acid, methanesulfonic acid, and vinegar The method according to any one of claims 1 to 7, wherein at least one selected from the group consisting of acids is used.

9. The method according to claim 8, wherein the non-optically active acid is hydrobromic acid.

0 The following general formula (1)

(Wherein, H X represents hydrobromic acid, methanesulfonic acid, or acetic acid). A salt of 1-benzyl-13-aminopyrrolidine represented by the formula:

11. The salt of 1-benzyl-3-aminopyrrolidine according to claim 10, which is an optically active substance.